MOTS-c: research background
What the compound is
MOTS-c (mitochondrial open reading frame of the 12S rRNA-c) is a signaling peptide composed of 16 amino acids (PMID 25738459, PMID 36761202). It is encoded by a short open reading frame (sORF) within the mitochondrial 12S rRNA (PMID 25738459, PMID 36761202). MOTS-c belongs to a group of mitochondrial-derived peptides (MDPs) encoded by the mitochondrial DNA (PMID 25738459, PMID 34520826).
How it is thought to work
MOTS-c primarily targets skeletal muscle, where it regulates insulin sensitivity and metabolic homeostasis (PMID 25738459, PMID 34798268). Its cellular actions involve inhibiting the folate cycle and associated de novo purine biosynthesis, which leads to the activation of AMPK (PMID 25738459). Under metabolic stress, MOTS-c is transferred to the nucleus, where it directs the expression of nuclear genes to promote cell balance (PMID 36761202). It is also known to directly bind to and activate casein kinase II (CK2) in cell-free systems, with tissue-specific effects on CK2 activity in fat and muscle (PMID 39559755). In lung injury models, MOTS-c's nuclear transport is dependent on MYH9 and it activates antioxidant genes such as HMOX1 and NQO1 (PMID 40403491). MOTS-c can also interact with LARS1 and promote its degradation (PMID 39321430).
What laboratory and animal studies report
In mice, MOTS-c treatment prevented age-dependent and high-fat-diet-induced insulin resistance, as well as diet-induced obesity (PMID 25738459). It has been shown to improve glucose metabolism in skeletal muscle (PMID 36761202). In gestational diabetes mellitus (GDM) mouse models, MOTS-c alleviated hyperglycemia, improved insulin sensitivity and glucose tolerance, and reduced birth weight and offspring death. It also activated insulin sensitivity in skeletal muscle and elevated glucose uptake in cells (in vitro), and protected pancreatic beta-cells from injury (PMID 34798268). Exogenous MOTS-c administration in rats attenuated lung injury by reducing oxidative damage, inflammation, and mortality (PMID 40403491). In ovarian cancer cells, exogenous MOTS-c inhibited proliferation, migration, and invasion, and induced cell cycle arrest and apoptosis (PMID 39321430). In mice, MOTS-c exhibited anti-tumor effects on ovarian cancer growth without systemic toxicity (PMID 39321430). MOTS-c administration to mice prevented skeletal muscle atrophy and enhanced muscle glucose uptake, effects that were reduced by suppressing CK2 activity (PMID 39559755). Young and aged mice treated with MOTS-c showed improved exercise capacity/performance, weight loss, increased antioxidant capacity, and improved insulin sensitivity (PMID 34520826). Many unapproved peptides, including MOTS-c, demonstrate favorable tissue repair and metabolic outcomes in animal models (PMID 41966639).
Human evidence so far
MOTS-c is present in plasma, but its level decreases with age in humans (PMID 36761202). Acute high-intensity exercise in humans can increase concentrations of MOTS-c in skeletal muscle and plasma (PMID 34520826). In a clinical context, serum MOTS-c increases within 24 hours post-cardiopulmonary bypass (CPB) outperformed traditional biomarkers in predicting acute respiratory distress syndrome (ARDS) incidence (PMID 40403491). A naturally occurring MOTS-c variant (K14Q MOTS-c), which has reduced binding to CK2, was associated with a higher risk of sarcopenia and type 2 diabetes in male carriers in an age- and physical-activity-dependent manner (PMID 39559755). Recent clinical studies have suggested a possible link between MOTS-c and human cancer, with MOTS-c levels found to be reduced in both serum and tumor tissues from ovarian cancer patients, which were associated with poorer patient prognosis (PMID 39321430). Rigorous human safety data for many unapproved peptides, including MOTS-c, are scarce (PMID 41966639).
Open questions and limitations
While MOTS-c shows therapeutic potential, no effective method of applying MOTS-c in the clinic has been developed (PMID 36761202). Research is needed to define the effect of exercise variables (mode, duration, intensity, participant characteristics) on mitochondrial-derived peptides like MOTS-c (PMID 34520826). There are distinct and overlapping pathways through which exercise and MOTS-c evoke metabolic benefits (PMID 34520826). The role of MOTS-c in tumorigenesis has been investigated, but further research is needed (PMID 39321430). Rigorous human safety data for many unapproved peptides, including MOTS-c, are scarce (PMID 41966639).
Key terms explained
AMPK (AMP-activated protein kinase) is an enzyme that plays a key role in cellular energy homeostasis (PMID 25738459). Insulin resistance occurs when cells in muscles, fat, and liver don't respond well to insulin, making it harder for glucose from the blood to enter cells (PMID 25738459). Hyperglycemia refers to high blood glucose (sugar) levels (PMID 34798268). Gestational diabetes mellitus (GDM) is a common complication during pregnancy where women who haven't been diagnosed with diabetes before pregnancy have high blood glucose levels (PMID 34798268). Ischemia-reperfusion injury (IRI) is tissue damage caused when blood supply returns to tissue after a period of lack of oxygen (ischemia) (PMID 40403491). Oxidative stress occurs when there is an imbalance between free radicals and antioxidants in the body, leading to cellular damage (PMID 40403491). Sarcopenia is the age-related loss of muscle mass, strength, and function (PMID 39559755). Ubiquitination and proteasomal degradation are processes involved in breaking down proteins within cells (PMID 39321430).
Studies cited in this section
- The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. — Cell metabolism, 2015 (PMID 25738459)
- MOTS-c: A promising mitochondrial-derived peptide for therapeutic exploitation. — Frontiers in endocrinology, 2023 (PMID 36761202)
- The mitochondrial-derived peptide MOTS-c relieves hyperglycemia and insulin resistance in gestational diabetes mellitus. — Pharmacological research, 2022 (PMID 34798268)
- MOTS-c attenuates lung ischemia-reperfusion injury via MYH9-Dependent nuclear translocation and transcriptional activation of antioxidant genes. — Redox biology, 2025 (PMID 40403491)
- Safety and Efficacy of Approved and Unapproved Peptide Therapies for Musculoskeletal Injuries and Athletic Performance. — Sports medicine (Auckland, N.Z.), 2026 (PMID 41966639)
- Mitochondrial-Derived Peptide MOTS-c Suppresses Ovarian Cancer Progression by Attenuating USP7-Mediated LARS1 Deubiquitination. — Advanced science (Weinheim, Baden-Wurttemberg, Germany), 2024 (PMID 39321430)
- Mitochondrial-derived peptides and exercise. — Biochimica et biophysica acta. General subjects, 2021 (PMID 34520826)
- MOTS-c modulates skeletal muscle function by directly binding and activating CK2. — iScience, 2024 (PMID 39559755)
Summarised from the PubMed abstracts listed above. Educational reference only — not medical advice or instructions.
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